Rheumatoid arthritis (RA) is an autoimmune disease which characteristically causes local inflammation in joints, deformation of joints, and bone destruction. Since inflammatory cytokines such as IL-1, IL-6, TNF-α, and IL-17 play significant roles in development of RA, antibodies and inhibitors against these cytokines are used for treatment of RA. Since high-titer autoantibodies are detected in sera of RA patients, antibodies against B cells are also useful for treatment of RA. These approaches have largely improved the effectiveness of RA treatment. However, since there are also patients for whom these treatments are not effective or become ineffective during the treatment, development of a novel therapeutic method has still been demanded.
The inventors previously generated two RA models; one is human T-cell leukemia virus type I (HTLV-I) transgenic (Tg) mice and the other is IL-1 receptor antagonist (IL-1Ra) deficient (KO) mice, both of which spontaneously develop autoimmune arthritis. Because multiple genes are implicated in the development of autoimmune diseases, the inventors searched for novel disease-related genes using DNA microarray techniques. As a result of comprehensive gene expression analysis between RA models and wild-type (WT) mice, the inventors identified 554 genes of which expression changed more than 3 times in both RA models compared with WT mice (N. Fujikado et al., Arthritis Res Ther 8 (2006) R100). The C1qtnf3 gene, which encodes CTRP3 (also named CORS-26, cartducin and cartnectin), is one of such genes and is highly expressed in both models.
CTRP3 is a soluble secreted protein consisted of a short N-terminal variable region, collagen domain and C-terminal complement C1q domain (R. Ghai et al., Immunobiology 212 (2007) pp. 253-266.). CTRP3 belongs to a member of C1q/TNF-related protein (CTRP) family (L. Shapiro et al., Curr Biol 8 (1998) pp. 335-338.), having a crystal structure resembling that of TNF and complement C1q (J. R. Dunkelberger et al, Cell Res 20 (2010) pp. 34-50). Previous reports showed that C1q domain of complement C1q is important for the recognition of antigen-bound IgM or IgG and binding to C1q receptor (C1qR) and also, C1q domain of adiponectin is important for the binding to adiponectin receptors (adipoR1 and adipoR2). CTRP family members are involved in host defense, inflammation and glucose metabolism (R. Ghai et al., Immunobiology 212 (2007) pp. 253-266.). CTRP3 is identified as a growth factor, and promotes proliferation of chondrogenic precursors and chondrocytes (T. Maeda et al., J Cell Physiol 206 (2006) pp. 537-544). Recently, it was reported that CTRP3 reduces an inflammatory cytokine secretion from human adipocytes, monocytes and fibroblasts in vitro (A. Kopp et al., Endocrinology 151 (2010) pp. 5267-5278, J. Weigert et al., FEBS Lett 579 (2005) pp. 5565-5570, C. Hofmann et al., Inflamm Bowel Dis 17 (2011) pp. 2462-2471).